Chronic exposure to arsenic in drinking water has been linked recently to cardiovascular disease. The heart and vasculature are the first organ system to form during development making it highly vulnerable to defects and adult disease due to fetal exposure to toxicants. In this regard, there is increased incidence in first trimester miscarriages, which are likely due to structural heart defects, in communities exposed to high levels of arsenic. Further, populations exposed to arsenic through contaminated drinking water have increased incidences of both heart and vascular diseases. The correct program of gene expression related to cardiovascular development and maintenance is essential and we have initial observations showing disruption by arsenic on key factors in this process. Specifically extracellular matrix (ECM) and TGFbeta2 are down-regulated by arsenic exposure during critical developmental periods for normal heart structure formation. The ECM component hyaluronan and TGFbeta2 are required for epithelial to mesenchymal transition (EMT) to contribute cardiac mesenchyme for heart valve formation and partitioning of the chambers. We will determine in Aim 1 whether arsenic attenuates these critical factors in vitro and in vivo. In Aim 2 we will determine the extent of disruption in valve formation which can lead to valve prolapse and disease later in life. We further show in adult mice that the ECM is disrupted by arsenic ingestion altering the vascular integrity predisposing the animals to vascular disease. Connective tissue disorders have mitral valve prolapse in addition to aortic aneurysisms and ruptures, with the later condition being already linked to arsenic. The ECM contains critical molecular targets for the effects of arsenic on the cardiovascular; however, the mechanisms responsible for these outcomes are not known. Although arsenic may not cause severe enough structural heart defects to abort fetal or neonatal development, subtle alterations may translate into disease predisposition in adults. As disease in adults is speculated to have origins during development, we will determine if fetal-arsenic exposure relates to structural heart valve defects, and vessel pathologies leading to heart disease.